A Novel Composite Endpoint to Evaluate the Gastrointestinal (GI) Effects of Nonsteroidal Antiinflammatory Drugs Through the Entire GI Tract

2009 ◽  
Vol 37 (1) ◽  
pp. 167-174 ◽  
Author(s):  
FRANCIS K. L. CHAN ◽  
BYRON CRYER ◽  
JAY L. GOLDSTEIN ◽  
ANGEL LANAS ◽  
DAVID A. PEURA ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Composite Endpoint ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Gi Tract ◽  
Antiinflammatory Drugs ◽  
Open Label ◽  
Upper Gi ◽  
Standard Tool ◽  
Gi Toxicity ◽  
Clinically Significant

Objective.Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage.Methods.We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed.Results.Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia.Conclusion.By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.

scholarly journals Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications

2014 ◽  
Vol 16 (5) ◽  
pp. 821 ◽  
Author(s):  
Sam Harirforoosh ◽  
Waheed Asghar ◽  
Fakhreddin Jamali
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Gi Tract ◽  
Antiinflammatory Drugs ◽  
Controlled Release Formulations ◽  
Gi Toxicity ◽  
Inflammatory Drugs ◽  
Cox 2

Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor’s files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Use of Nonsteroidal Antiinflammatory Drugs: Is There a Change in Patient Risk Profile After Withdrawal of Rofecoxib?

2010 ◽  
Vol 38 (2) ◽  
pp. 195-202 ◽  
Author(s):  
ELHAM RAHME ◽  
JEAN-PASCAL ROUSSY ◽  
JEAN-PHILIPPE LAFRANCE ◽  
HACENE NEDJAR ◽  
SUZANNE MORIN
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Risk Profile ◽  
Antiinflammatory Drugs ◽  
Risk Levels ◽  
Gi Toxicity ◽  
To Receive ◽  
Very High ◽  
Post Period

Objective.Use of traditional nonsteroidal antiinflammatory drugs (tNSAID) increased after rofecoxib withdrawal. tNSAID use is associated with increased gastrointestinal (GI) toxicity and cardiovascular (CV) risk similar to celecoxib. The objective of our study was to describe changes in celecoxib and tNSAID use regarding GI and CV risk and congestive heart failure (CHF) and renal risk that occurred in Quebec, Canada, between April 2005–March 2007 (the post-period) compared to April 2002–March 2004 (the pre-period).Methods.Data were obtained from the provincial health insurance agency. All NSAID users ≥ 50 years of age were considered.Results.Celecoxib use decreased by 23% (coxib 61%) while that of tNSAID doubled. In both periods, celecoxib users were older and included more women, and they suffered more frequently from arthritis. Users of celecoxib were more likely to have higher level of GI risk: post-period odds ratios compared to low GI risk, very high 1.79 (95% CI 1.63, 1.97), high 1.76 (95% CI 1.71, 1.81), and moderate 1.30 (95% CI 1.27, 1.33); similar results were observed in the pre-period. Celecoxib users had higher CV risk levels in the pre-period: OR compared to low CV risk, very high 1.13 (95% CI 1.08, 1.19), high 1.24 (95% CI 1.20, 1.29), and moderate 1.16 (95% CI 1.14, 1.19); and in the post-period, very high 0.85 (95% CI 0.81, 0.89), high 1.13 (95% CI 1.10, 1.16), and moderate 1.15 (95% CI 1.12, 1.17). CHF and renal risk factors did not play an important role in the choice of NSAID in either period.Conclusion.Current NSAID use differs from that prior to 2004. Coxib utilization decreased substantially and patients at high CV risk seem less likely to receive celecoxib, while those at high GI risk seem more likely to receive it.

Aspirin Synergistically Potentiates Isoflurane Minimum Alveolar Concentration Reduction Produced by Morphine in the Rat 

1998 ◽  
Vol 89 (6) ◽  
pp. 1489-1494 ◽  
Author(s):  
Ignacio A. Gomez de Segura ◽  
Ana B. Criado ◽  
Martin Santos ◽  
Francisco J. Tendillo
Keyword(s):  
Side Effects ◽  
Minimum Alveolar Concentration ◽  
Synergistic Effects ◽  
Objective Measure ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Before And After ◽  
Male Wistar Rats ◽  
Clinically Significant ◽  
Analgesic Potency

Background The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. Methods Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. Results Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. Conclusions The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.

scholarly journals Cancer Chemoprevention: Successes and Failures

2013 ◽  
Vol 59 (1) ◽  
pp. 94-101 ◽  
Author(s):  
Sherri L Patterson ◽  
Karen Colbert Maresso ◽  
Ernest Hawk
Keyword(s):  
Randomized Clinical Trials ◽  
Precancerous Lesions ◽  
Cancer Chemoprevention ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Regulatory Approval ◽  
Antiinflammatory Drugs ◽  
End Points ◽  
Chemopreventive Agents ◽  
The Many ◽  
Prevention Potential

BACKGROUND Cancer has traditionally been considered a single disease, but it is now known to be far more complex, with an unfolding etiology. In less than 2 centuries, hundreds—if not thousands—of drugs for the treatment of cancer and for palliative care have been developed and tested, with 143 having achieved approval by the US Food and Drug Administration (MediLexicon International; “Cancer Drugs & Oncology Drugs,” http://www.medilexicon.com/drugs-list/cancer.php). Just 13 agents have been approved, however, for treating precancerous lesions or for reducing risk. CONTENT Nonsteroidal antiinflammatory drugs, vitamins, food constituents and spice components, antidiabetic drugs, ω-3 fatty acids, and fiber are just a few of the many classes of compounds that have been tested for their cancer-preventive potential. We highlight some of the agents that have been scrutinized by way of randomized clinical trials in humans for their cancer prevention potential. We summarize the major definitive cancer chemoprevention studies that (a) were successful in demonstrating efficacy and ultimately received regulatory approval; (b) were not successful in demonstrating efficacy or had unacceptable toxicities, but from which the field has learned important lessons; and (c) showed compelling efficacy against surrogate end points but failed to achieve regulatory approval because of a lack of consensus regarding the relevance of those end points to clinical benefit. SUMMARY Chemopreventive studies have provided new insights into early disease pathogenesis, stimulated new risk assessments and models, fostered important research in end point biomarkers, and led to 13 approved agents. The development of safe and effective chemopreventive agents holds tremendous potential for reducing the burden of cancer.

Methotrexate and Nonsteroidal Antiinflammatory Drug Interactions

1992 ◽  
Vol 26 (2) ◽  
pp. 234-237 ◽  
Author(s):  
Maureen L. Frenia ◽  
Kimberly S. Long ◽  
Edward A. Hartshorn
Keyword(s):  
Case Reports ◽  
Clinical Manifestations ◽  
Hepatic Metabolism ◽  
Antiinflammatory Drug ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Nonsteroidal Antiinflammatory Drug ◽  
Pharmacokinetic Studies ◽  
Hematologic Toxicity ◽  
Antiinflammatory Drugs ◽  
Clinically Significant

OBJECTIVE: To determine if the coadministration of methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAIDs) results in a clinically significant drug interaction. DATA SOURCES: A case report of hematologic toxicity following the administration of MTX and flurbiprofen at our institution is presented. Six previously published case reports and five pharmacokinetic studies regarding MTX and NSAID interactions are available to assist in the evaluation of this potential interaction. DATA SYNTHESIS: Cases of various clinical manifestations during concomitant MTX and NSAID administration, including acute renal failure and pancytopenia, have been reported. The exact mechanism of the interaction has not been fully elucidated. Suggested theories to explain the mechanism of MTX toxicity include reduction in MTX clearance secondary to renal capillary constriction induced by NSAIDs, displacement of MTX or its metabolite from plasma proteins, competition between MTX and NSAIDs for renal tubular excretion, or impairment of hepatic metabolism of MTX by NSAIDs. Studies comparing MTX pharmacokinetics with or without concurrent NSAID therapy have not shown statistical differences in the parameters evaluated. However, one study did demonstrate differences in the pharmacokinetics of 7-hydroxymethotrexate, the active metabolite of MTX, when MTX was administered with aspirin. CONCLUSIONS: Although a clinically significant interaction does not occur in all patients, numerous case reports are available that demonstrate possible problems following the coadministration of MTX and NSAIDs. To date, the specific circumstances during which the reaction may occur have not been well defined.

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